U.S. patent number 6,743,803 [Application Number 10/311,932] was granted by the patent office on 2004-06-01 for medicines for the prevention and treatment of neurodegenerative diseases.
This patent grant is currently assigned to Dainippon Pharmaceutical Co., Ltd.. Invention is credited to Kiyoshi Furukawa, Satoshi Kurumiya, Kazunori Ohno, Kazuo Okimoto.
United States Patent |
6,743,803 |
Furukawa , et al. |
June 1, 2004 |
**Please see images for:
( Certificate of Correction ) ** |
Medicines for the prevention and treatment of neurodegenerative
diseases
Abstract
Medicines for the prevention and treatment of neurodegenerative
diseases such as Alzheimer's disease and schizophrenia of mammals
(including human beings) through the retardation or inhibition of
neurodegeneration due to hypofunction of glutamic acid receptor and
which contain as an active ingredient
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives
of the formula (I): ##STR1## wherein Het is oxadiazolyl; R.sup.1 is
hydrogen, lower alkyl, cyclo-lower alkyl, lower alkenyl, lower
alkoxy, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, etc.; and R.sup.2 is hydrogen, lower
alkyl, cyclo-lower alkyl, substituted or unsubstituted aryl, etc.,
or physiologically acceptable acid addition salts thereof.
Inventors: |
Furukawa; Kiyoshi (Shiga-gun,
JP), Kurumiya; Satoshi (Nishinomiya, JP),
Okimoto; Kazuo (Osaka, JP), Ohno; Kazunori
(Ikoma, JP) |
Assignee: |
Dainippon Pharmaceutical Co.,
Ltd. (Osaka-Fu, JP)
|
Family
ID: |
18686074 |
Appl.
No.: |
10/311,932 |
Filed: |
December 20, 2002 |
PCT
Filed: |
June 12, 2001 |
PCT No.: |
PCT/JP01/04934 |
PCT
Pub. No.: |
WO01/98300 |
PCT
Pub. Date: |
December 27, 2001 |
Foreign Application Priority Data
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Jun 21, 2000 [JP] |
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2000-185814 |
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Current U.S.
Class: |
514/300;
546/122 |
Current CPC
Class: |
A61K
31/444 (20130101); C07D 471/04 (20130101); A61P
25/28 (20180101); A61K 31/4375 (20130101); A61P
25/18 (20180101); A61P 25/00 (20180101) |
Current International
Class: |
A61K
31/4353 (20060101); A61K 31/444 (20060101); A61K
31/4375 (20060101); C07D 471/04 (20060101); A61K
31/4427 (20060101); C07D 471/00 (20060101); A61K
031/437 (); C07D 471/04 () |
Field of
Search: |
;514/300,299
;546/122 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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5-221997 |
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Aug 1993 |
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JP |
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9-291034 |
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Nov 1997 |
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JP |
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99/03857 |
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Jan 1999 |
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WO |
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00/73283 |
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Dec 2000 |
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WO |
|
Other References
Elliot D. Luby, M.D., et al., "Study of a New Schizophrenomimetic
Drug-Sernyl", Archives of Neurology and Psychiatry, vol. 81, pp.
363-369, 1959. .
Gaylord Ellison, "The N-methyl-D-aspartate antagonists
phencyclidine, ketamine and dizocilpine as both behavioral and
anatomical models of the dementias", Brain Research Reviews, 20,
pp. 250-267, 1995. .
D.F. Wozniak et al., "MK-801 neurotoxicity in male mice: histologic
effects and chronic impairment in spatial learning" 707, pp.
165-179, 1996. .
John W. Olney et al., "NMDA receptor hyopfunction model of
schizophrenia", Journal of Psychiatric Research, 33, pp. 523-533,
1999. .
Pete Andine, et al., "Characterization of MK-801-Induced Behavior
as a Putative Rat Model of Psychosis", Journal of Pharmacol.
Experimental Therapeutics, vol. 290, pp. 1393-1408, 1999. .
J.W. Olney, et al., "NMDA Antagonist Neurotoxicity: Mechanism and
Prevention", Science, vol. 254, pp. 1515-1518, 1991..
|
Primary Examiner: Aulakh; Charanjit S.
Attorney, Agent or Firm: Wenderoth, Lind & Ponack,
L.L.P.
Claims
What is claimed is:
1. A method for treatment of schizophrenia in a mammal which
comprises administering to a mammal in need of such treatment of
schizophrenia an effective amount of a
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative
of the following formula (I): ##STR4##
wherein: Het is an oxadiazolyl group; R.sup.1 is a hydrogen atom, a
lower alkyl group, a cyclo-lower alkyl group, a trifluoromethyl
group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy
group, a lower alkoxy-lower alkyl group, a hydroxy-lower alkyl
group, a substituted or unsubstituted aryl group, or a substituted
or unsubstituted heteroaryl group; and R.sup.2 is a hydrogen atom,
a lower alkyl group, a cyclo-lower alkyl group, a cyclo-lower
alkylmethyl group, a lower alkenyl group, a cyclo-lower alkenyl
group, a lower alkynyl group, a substituted or unsubstituted aryl
group, or a substituted or unsubstituted heteroaryl group, or a
physiologically acceptable acid addition salt thereof.
2. The method according to claim 1, wherein the mammal is a
human.
3. The method according to claim 1, wherein R.sup.1 is a C.sub.1 to
C.sub.3 alkyl group, a C.sub.3 to C.sub.4 cycloalkyl group, or a
C.sub.2 to C.sub.3 alkenyl group, and R.sup.2 is a hydrogen atom, a
C.sub.1 to C.sub.4 alkyl group, a C.sub.3 to C.sub.6 cycloalkyl
group, a substituted or unsubstituted aryl group, or a substituted
or unsubstituted heteroaryl group.
4. The method according to claim 1, wherein the mammal is a
human.
5. The method according to claim 1, wherein R.sup.1 is a C.sub.1 to
C.sub.3 alkyl group or C.sub.3 to C.sub.4 cycloalkyl group, and
R.sup.2 is a hydrogen atom, a C.sub.1 to C.sub.3 alkyl group, a
C.sub.3 to C.sub.4 cycloalkyl group, a substituted or unsubstituted
phenyl group, or a substituted or unsubstituted heteroaryl
group.
6. The method according to claim 5, wherein the mammal is a
human.
7. A method for treatment of schizophrenia in a mammal which
comprises administering to a mammal in need of such treatment of
schizophrenia an effective amount of a
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative
selected from the group consisting of
3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-methylcyclopropyl)-1,6-naphthyridin-2
(1H)-one,
3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)
-one,
3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(4-methoxyphenyl)-1,6-naphthyridine-2(1
H)-one,
3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-thienyl)-1,6-naphthyridin-2(1H)-one,
3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(4-pyridyl)-1,6-naphthyridin-2(1H)-one,
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-methyl-1,6-naphthyridin-2(1H)-one,
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(3-fluorophenyl)-1,6-naphthyridin-2(1H)-
one,
3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methylphenyl)-1,6-naphthyridin-2(I
H)-one,
3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H
)-one,
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-methoxyphenyl)-1,6-naphthyridin-2(1H)
-one,
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-pyridyl)-1,6-naphthyridin-2(1H)-one,
3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(3-thienyl)-1,6-naphthyridin-2(1H)
-one, and a physiologically acceptable acid addition salt
thereof.
8. The method according to claim 7, wherein the mammal is a
human.
9. A method for treatment of schizophrenia in a mammal which
comprises administering to a mammal in need of such treatment of
schizophrenia an effective amount of
3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1
H)-one or a physiologically acceptable acid addition salt
thereof.
10. The method according to claim 9, wherein the mammal is a human.
Description
TECHNICAL FIELD
The present invention relates to a medicine for the prevention and
treatment of neurodegenerative diseases comprising a
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative
or a physiologically acceptable acid addition salt thereof as an
active ingredient, and use of said compound for the manufacture of
a medicine for the prevention and treatment of neurodegenerative
diseases.
BACKGROUND ART
With developing into an aging society, the number of patients
suffering from neurodegenerative diseases such as Alzheimer's
disease is increasing. Alzheimer's disease is a progressive
neurodegenerative disorder of the central nervous system which
symptoms are mainly attenuation and decline of memory, and it is
suggested by the neurochemical studies that the main cause is
dysfunction of neurotransmissions in plural neurotransmitter
systems such as acetylcholine, .gamma.-aminobutyric acid (GABA),
glutamic acid, and dopamine. On the basis of the finding that the
neuronal dysfunction occurs remarkably in cholinergic system among
those systems, a medicine has been developed for the purpose of
improvement in cognitive deficits by means of the activation of
cholinergic system.
Besides, there are also some attempts to develop benzodiazepine
(BZP) receptor inverse agonists as the therapeutic agent for
treatment of dementia. Heretofore, many studies have been done on
the relationship between the binding-manner to the BZP receptor and
the pharmacological activity, and in view of the pharmacological
activity thereof, BZP agonists have been used as antianxiety drugs
(e.g. diazepam), as hypnotics (e.g. triazolam), or as antiepileptic
drugs (e.g. clonazepam). However, it is well-known that
administration of BZP agonists causes amnesia (amnesic action) as a
side effect. On the other hand, since it is known that BZP inverse
agonists exhibit the actions opposite to those of BZP agonists, and
enhance cholinergic activity which is considerably related with
cognitive function, the inverse agonist is expected to have the
anti-dysmnesia action (anti-amnesia action) and to activate
cerebral function.
As an example of such a compound, WO 99/03857 discloses
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives
of the following formula: ##STR2##
wherein Het is an oxadiazolyl group; R.sup.1 is a hydrogen, a lower
alkyl group, a cyclo-lower alkyl group, a lower alkenyl group, a
lower alkoxy group, a substituted or unsubstituted aryl group, a
substituted or unsubstituted heteroaryl group, etc.; and R.sup.2 is
a hydrogen, a lower alkyl group, a cyclo-lower alkyl group, a
substituted or unsubstituted aryl group, etc.,
in which it is described that said compounds exhibit selective and
high affinity to benzodiazepine receptor and are useful as
benzodiazepine receptor ligands, especially as inverse agonists,
which are expected to be cerebral activators or therapeutic agents
for treatment of senile dementia and Alzheimer's disease.
Recently, it has been indicated that schizophrenia and Alzheimer's
disease are related with the hypofunction of ion-channel type
N-methyl-D-aspartic acid (hereinafter, abbreviated to "NMDA")
receptor, which is a subtype of glutamic acid receptors.
Phencyclidine, a noncompetitive antagonist of NMDA receptor,
exhibits excellent pharmacological activities such as anesthetic
activity and neuroprotective activity for acute encephalopathy,
while it has been ever used for the undesirable purpose of
extensive drug abuse as street drug. After E. D. Luby et al.
reported that phencyclidine caused schizophrenia-like hallucination
and mental aberration in human beings [Archives Neurology and
Psychiatry. Vol 81, pp 363-369 (1959)], a lot of studies thereof
have been accumulated until today. It has been proved that
phencyclidine causes schizophrenia-like hallucination and mental
aberration in human beings more strongly than amphetamine or LSD
(9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8.beta.-carboxamide).
Additionally, in the case of animals, it is known that NMDA
receptor antagonists such as phencyclidine, MK-801 (dizocilpine
maleate:
(+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine
maleate) and ketamine, cause the enhancement of spontaneous motor
activity and aberrant behaviors related with the symptoms of mental
aberration such as hallucination, as well as ataxia, and such
behavioral changes are suppressed by medicines for schizophrenia
(e.g. haloperidol, risperidone and olanzapine), antianxiety drugs
(e.g. diazepam), and antagonists of NMDA receptor glycine site
(e.g. HA-966: R(+)-3-amino-1-hydroxy-2-pyrrolidinone). It is also
known that NMDA receptor antagonists (MK-801, phencyclidine and
ketamine) cause learning/memory disorder in animals. Consequently,
a medicine suppressing hypofunction of NMDA receptor is expected to
be useful for therapy of dysmnesia and schizophrenia.
It is known that MK-801 is a noncompetitive antagonist for NMDA
receptor, which is a subtype of glutamate receptors, and encephalic
neuronopathy (leading to cell death via cell vacuolization) is
caused by the systemic administration of said agent to animals.
That is, in the case of the single application of MK-801 at
moderate doses (0.3-1.0 mg/kg), neuronal vacuolization is observed
in the posterior cingulate (PC)/retrosplenial cortex (RS)
(hereinafter, abbreviated to PC/RS cortex) in 4-5 hours after
administration, and in the case of higher doses (3-10 mg/kg),
necrosis of neurons and hyperplasia of glial cells are observed in
a few days to a few weeks after administration. Besides, in the
case of repeated application, the damage spreads to hippocampal
ventral dentate gyrus and limbic regions such as entorhinal cortex
and amygdala. It is presumed that the hypofunction of NMDA receptor
may cause neurodegeneration in the PC/RS cortex through complicated
polysynaptic network mechanism [in which at least 7 receptors, i.e.
glutamic acid (NMDA and non-NMDA), acetylcholine-M3,
adrenaline-.alpha.2, GABA-A, sigma and serotonin 2A, are involved],
since such neurodegeneration would be caused by both noncompetitive
antagonists of NMDA receptor (phencyclidine and ketamine) and
competitive antagonists [e.g. D-2-amino-5-phosphono-pentanoic acid
(D-AP5)]. It is considered that the dysfunction of NMDA receptor
caused by administration of MK-801 may be closely related to the
onset of neurodegenerative diseases, and hence the neuronopathy
induced by MK-801 will be usable as a pathological model of
neurodegenerative diseases [see, G. Ellison. Brain Research
Reviews. Vol 20, pp 250-267 (1995); D. F. Wozniak et al., Brain
Research. Vol 707, pp 165-179 (1996); J. W. Olney et al., J.
Psychiatric Research. Vol 33, pp 523-533 (1999); P. Andine et al.,
J. Pharmacol. Exp. Ther., Vol 290, pp 1393-1408 (1999)].
It is known that medicines inhibiting MK-801-induced neuronopathy
include anticholinergic drugs (e.g. scopolamine and atropine),
barbiturate hypnotics (e.g. pentobarbital and thiopental), and
benzodiazepine derivatives (e.g. diazepam) [see, J. W. Olney et
al., Science, Vol 254, pp 1515-1518 (1991)].
The present inventors have found that
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives
of the formula (I) or physiologically acceptable acid addition
salts thereof exhibit an extremely potent inhibitory effect on the
MK-801-induced neurodegeneration in the PC/RS cortex by using the
above pathological model.
DISCLOSURE OF INVENTION
An object of the present invention is to provide a medicine for the
prevention and treatment of neurodegenerative diseases comprising a
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative
of the following formula (I): ##STR3##
wherein: Het is an oxadiazolyl group; R.sup.1 is a hydrogen atom, a
lower alkyl group, a cyclo-lower alkyl group, a trifluoromethyl
group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy
group, a lower alkoxy-lower alkyl group, a hydroxy-lower alkyl
group, a substituted or unsubstituted aryl group, or a substituted
or unsubstituted heteroaryl group; and R.sup.2 is a hydrogen atom,
a lower alkyl group, a cyclo-lower alkyl group, a cyclo-lower
alkylmethyl group, a lower alkenyl group, a cyclo-lower alkenyl
group, a lower alkynyl group, a substituted or unsubstituted aryl
group, or a substituted or unsubstituted heteroaryl group, or a
physiologically acceptable acid addition salt thereof.
Another object of the present invention is to provide use of a
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative
of the formula (I) or a physiologically acceptable acid addition
salt thereof for the manufacture of a medicine for the prevention
and treatment of neurodegenerative diseases.
A further object of the present invention is to provide a method
for the prevention and/or treatment of neurodegenerative diseases
in mammals (including human beings), which comprises administering
an effective amount of a
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative
of the formula (I) or a physiologically acceptable acid addition
salt thereof to said mammals in need of such prevention and/or
treatment.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors have found that the
5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative
of the above formula (I) can be used for the prevention and/or
treatment of neurodegenerative diseases with hypofunction of
glutamic acid receptor, such as Alzheimer's disease or
schizophrenia, in mammals (including human beings).
The compounds used for the prevention and treatment of
neurodegenerative diseases of the present invention are shown by
the formula (I), and the preferred compounds are those of the
formula (I) wherein R.sup.1 is a C.sub.1 -C.sub.3 alkyl group, a
C.sub.3 -C.sub.4 cycloalkyl group, or a C.sub.2 -C.sub.3 alkenyl
group; and R.sup.2 is a hydrogen atom, a C.sub.1 -C.sub.4 alkyl
group, a C.sub.3 -C.sub.6 cycloalkyl group, a substituted or
unsubstituted aryl group, or a substituted or unsubstituted
heteroaryl group.
More preferred compounds are those of the formula (I) wherein
R.sup.1 is a C.sub.1 -C.sub.3 alkyl group or a C.sub.3 -C.sub.4
cycloalkyl; and R.sup.2 is a hydrogen atom, a C.sub.1 -C.sub.3
alkyl group, a C.sub.3 -C.sub.4 cycloalkyl group, a substituted or
unsubstituted phenyl group, or a substituted or unsubstituted
heteroaryl group.
Further more preferred compounds are the following compounds;
3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-methylcyclo-propyl)-1,6-naphthyridin-
2(1H)-one,
3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)
-one,
3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H
)-one,
3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(4-methoxyphenyl)-1,6-naphthyridin-2(1H
)-one,
3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-thienyl)-1,6-naphthyridin-2(1H)-one,
3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(4-pyridyl)-1,6-naphthyridin-2(1H)-one,
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-methyl-1,6-naphthyridin-2(1H)-one,
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(3-fluorophenyl)-1,6-naphthyridin-2(1H)-
one,
3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methylphenyl)-1,6-naphthyridin-2(1H)
-one,
3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H
)-one,
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-methoxyphenyl)-1,6-naphthyridin-2(1H)
-one,
3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-pyridyl)-1,6-naphthyridin-2(1H)-one,
and
3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(3-thienyl)-1,6-naphthyridin-2(1H)
-one.
Suitable examples of physiologically acceptable acid addition salts
of the compounds of the formula (I) are inorganic acid salts such
as hydrochloride, hydrobromide, hydroiodide, sulfate, or phosphate,
and organic acid salts such as oxalate, maleate, fumarate,
malonate, lactate, malate, citrate, tartrate, benzoate,
methanesulfonate, or tosylate.
The "lower alkyl group" and "lower alkyl" moiety in the present
description denote a straight chain or branched chain alkyl group
having 1-6 carbon atoms, such as methyl group, ethyl group, propyl
group, isopropyl group, butyl group, isobutyl group, tert-butyl
group, pentyl group, and hexyl group.
The "cyclo-lower alkyl group" denotes a cycloalkyl group having 3-6
carbon atoms, such as cyclopropyl group, cyclobutyl group,
cyclopentyl group, and cyclohexyl group, and these rings may be
optionally substituted by a C.sub.1 -C.sub.3 alkyl group or a
halogen atom.
The "lower alkenyl group" and "lower alkynyl group" have a straight
or branched carbon chain having 2-6 carbon atoms, and include, for
example, allyl group, 1-propenyl group, propargyl group, and
2-methyl-1-ethynyl group.
The "cyclo-lower alkenyl group" denotes a cycloalkenyl group having
5-6 carbon atoms, such as cyclohexenyl group.
The "lower alkoxy group" and "lower alkoxy" moiety denote a
straight chain or branched chain alkoxy group having 1-6 carbon
atoms, such as methoxy group, ethoxy group, propoxy group,
isopropyloxy group, butyloxy group, isobutyloxy group,
tert-butyloxy group, pentyloxy group, and hexyl group.
The "aryl group" and "aryl" moiety denote a phenyl group or a
naphthyl group, and said ring may optionally have 1-3 substituents
selected from a halogen atom, a C.sub.1 -C.sub.3 alkyl group, a
trifluoromethyl group, a hydroxy group, a C.sub.1 -C.sub.3 alkoxy
group, a trifluoromethoxy group, a cyano group, an amino group, and
a nitro group.
The "heteroaryl group" denotes a 5- to 6-membered aromatic
heterocyclic group containing 1-2 hetero atoms, which are, the same
or different, selected from nitrogen atom, oxygen atom or sulfur
atom, and includes, for example, furyl, thienyl, pyrrolyl,
oxazolyl, isoxazolyl, pyridyl, pyridazinyl, and pyrimidinyl,
wherein such heterocyclic group may optionally have 1 to 3
substituents selected from a halogen atom, a C.sub.1 -C.sub.3 alkyl
group, a hydroxy group, a C.sub.1 -C.sub.3 alkoxy group, and an
amino group.
Further, the "halogen atom" denotes fluorine atom, chlorine atom,
bromine atom or iodine atom.
The compounds of the formula (I) can be prepared by the method
disclosed in WO99/03857.
Pharmacological Experiments
The utility of the compounds of the formula (I) as the medicine for
prevention and treatment of neurodegenerative diseases will be
illustrated by the following pharmacological tests using a model
for MK-801-induced neuronopathy and the results thereof as to the
typical compounds of the formula (I).
3-(5-Methyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H
)-one (hereinafter, referred to as "Compound A") was used as a test
compound. Compound A can be prepared according to the method
disclosed in PCT Publication WO 99/03857.
Further, MK-801 (dizocilpine maleate) is described in, for example,
Merck Index, 12th Edition, 3451 (1996), and is commercially
available, (for example, (+)MK-801, manufactured by Research
Biochemical International)
Experiment 1
Inhibitory Effect on MK-801-Induced Neurodegeneration
The pharmacological test was carried out according to the method of
D. F. Wozniak, et al. [Brain Research, Vol. 707, pp 165-178
(1996)].
MK-801 was dissolved in physiological saline (concentration 0.1
mg/ml) and was subcutaneously (s.c.) administered to three mice
(Std-ddY male mice: 39.9-45.8 g of body weight) in a volume of 0.1
ml per 10 g of body weight, i.e., 1 mg/kg. Compound A was suspended
in a 0.5% tragacanth solution in a concentration of 0.1 mg/ml, and
the resultant suspension was orally (p.o.) administered to the mice
in a volume of 0.1 ml per 10 g of body weight, i.e., 1 mg/kg, 30
minutes before MK-801 administration. Five hours after MK-801
administration, mice were perfused with physiological saline and
fixed with 10% neutral formalin buffer solution under etherization.
The cerebrum was cut transversely from the anterior termination at
approximately 4 mm to the posterior termination, and then embedded
in cold polymerized resin (Technovit7100, manufactured by Kulzer in
Germany). The slices containing the PC/RS cortex were obtained at
four Anterior-Posterior levels at intervals of 300 .mu.m from the
exposed section of the block, and at each level two slices (3 .mu.m
in thickness) were consecutively obtained. The histological change
(on Hematoxylin and eosin stain specimen) and the number of
vacuolized neurons (on Nissl stain specimen) were observed by a
light microscope for each 4 slices, respectively. The results are
shown in Table 1.
Table 1 shows the number of vacuolized neurons in the PC/RS cortex
in the non-treated control group, the group treated with MK-801
alone, and the group treated with Compound A before MK-801.
As shown in Table 1, in the group treated with MK-801 (1 mg/kg) for
5 hours, the vacuolization was remarkably observed in the neurons
of layers III-IV, and the mean number of the vacuolized neurons per
mouse remarkably increased from 0 (in non-treated control group) to
30.8 per slice. On the contrary, in the group treated with Compound
A (1 mg/kg) prior to MK-801, the number remarkably decreased to
4.3, and in some of them no vacuolization was observed.
TABLE 1 Vacuolization Animal Slice No. Mean(/slice) Test Group No.
1 2 3 4 Individual Group Non-treatment 01M01 0 0 0 0 0.0 0.0
control group 01M02 0 0 0 0 0.0 01M03 0 0 0 0 0.0 MK-801 02M01 41
50 34 19 36.0 30.8 1 mg/kg s.c. 02M02 23 39 42 40 36.0 5 h group
02M03 26 24 14 17 20.3 Compound A 03M01 0 0 0 0 0.0 4.3 1 mg/kg
p.o. + 03M02 20 12 10 5 11.8 MK-801 03M03 0 0 2 2 1.0 1 mg/kg s.c.
5 h group
As is clear from the above results, Compound A exhibited a potent
retardation or inhibition of neurodegeneration in the PC/RS cortex
induced by MK-801. Accordingly, the compounds (I) of the present
invention are useful for the treatment of Alzheimer's disease or
schizophrenia, as a medicine for the prevention and treatment of
neurodegenerative diseases on the basis of inhibitory effect on
neurodegeneration, through the different mechanism from that of the
current medicines for the improvement in neural hypofunction via
the activation of cholinergic function.
Usage of Compounds of the Invention as Medicine
The compounds of the formula (I) can be used as a medicine for the
prevention and treatment of neurodegenerative diseases. They can be
administered through any of oral, parenteral and intrarectal
routes, preferably oral route. The dosage thereof may vary
depending on the administration route, kinds of diseases to be
treated, symptom/age of patients, deal mode (prevention or
treatment), etc., but it is usually in 0.01 to 10 mg/kg/day,
preferably 0.02 to 5 mg/kg/day, which may be administered at one
time or dividedly in several times.
The compounds of the formula (I) can be used as a medicine for the
prevention and treatment of neurodegenerative diseases alone or in
the form of a pharmaceutical composition, which is generally
prepared by mixing with a pharmaceutically acceptable carrier. The
pharmaceutical composition may be in the dosage forms such as
tablets, capsules, granules, powders, syrups, suspensions,
suppositories, gels, sustained release preparations, and injection
preparations. These pharmaceutical compositions can be prepared by
a conventional method. The pharmaceutically acceptable carrier may
be any conventional ones, which are commonly used in the
pharmaceutical field and do not react with the compounds of the
present invention. Suitable examples are lactose, glucose,
mannitol, dextrin, starch, corn starch, sucrose, polysaccharide,
magnesium aluminometasilicate, synthetic aluminum silicate,
crystalline cellulose, sodium carboxymethylcellulose, calcium
carboxymethylcellulose, hydroxypropyl starch, ion exchange resins,
methylcellulose, gelatin, acacia, hydroxypropylcellulose,
low-substituted hydroxypropylcellulose,
hydroxypropylmethylcellulose, poly-vinylpyrrolidone, polyvinyl
alcohol, light anhydrous silicic acid, magnesium stearate, talc,
carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester,
sodium lauryl sulfate, glycerin, glycerin fatty acid ester,
purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable
oil, wax, liquid paraffin, white petrolatum, nonionic surfactant,
propylene glycol, and water.
Liquid preparations may be in the form, which is dissolved or
suspended in water or other appropriate medium when used. Further,
tablets and granules may be coated in a conventional manner. In the
case of suppositories, the base for them includes cacao butter,
glycerin saturated fatty acid ester, glycerogelatin, macrogol,
etc., and in the preparations, a surfactant or a preservative may
optionally be added. Injection preparations may be prepared by
dissolving a physiologically acceptable acid addition salt of the
compound of the formula (I) in distilled water for injection or
physiological saline, and thereto may be optionally added a
solubilizer, an isotonic agent, a pH adjusting agent, a buffering
agent, a pain-reducing agent or a preservative.
These pharmaceutical compositions may usually contain the compound
of the formula (I) as an active ingredient in an amount of at least
0.01% by weight, preferably 0.05-70% by weight. These
pharmaceutical compositions may optionally contain other
therapeutically effective compounds.
Preparation
The pharmaceutical compositions of the medicine for the prevention
and treatment of neurodegenerative diseases according to the
present invention are illustrated by the following
preparations.
Preparation 1: Capsules: 3-(5-Methyl-1,2,4-oxadiazol-3-yl)- 5 g
5-(3-methoxyphenyl)-1,6-naphthyridin- 2 (1H)-one Corn starch 57 g
Lactose 10 g Crystalline cellulose 25 g Hydroxypropylcellulose 2 g
Light anhydrous silicic acid 0.5 g Magnesium stearate 0.5 g
Amongst the above components, the active ingredient, corn starch,
lactose and crystalline cellulose are blended, and thereto is added
hydroxypropylcellulose being dissolved in water, and the mixture is
kneaded, dried and granulated. To these granules are added
magnesium stearate and light anhydrous silicic acid and mixed.
These are filled in 1000 capsules to prepare the capsule
preparations weighing 100 mg each.
Preparation 2: Tablets: 3-(5-Methyl-1,2,4-oxadiazol-3-yl)- 5 g
5-(3-methoxyphenyl)-1,6-naphthyridin- 2 (1H)-one Corn starch 20 g
Lactose 19 g Crystalline cellulose 10 g Hydroxypropylcellulose 5 g
Low-substituted hydroxypropylcellulose 10 g Magnesium stearate 0.5
g Light anhydrous silicic acid 0.5 g
Amongst the above components, the active ingredient, corn starch,
lactose, low-substituted hydroxypropyl-cellulose and crystalline
cellulose are blended, and thereto is added hydroxypropylcellulose
being dissolved in water, and the mixture is kneaded, dried and
granulated. Thereto are added magnesium stearate and light
anhydrous silicic acid, and the mixture is compressed to give
tablet cores having the active ingredient weighing 5 mg content
(alternatively indicated as the weight of 70 mg each tablet). Then,
said tablet cores are coated to form film-coated tablets by a
conventional method, using hydroxypropylmethylcellulose, macrogol,
titanium oxide, talc and light anhydrous silicic acid.
Preparation 3: 1 % Powders: 3-(5-Methyl-1,2,4-oxadiazol-3-yl)- 5 g
5-(3-methoxyphenyl)-1,6-naphthyridin- 2 (1H)-one Corn starch 150 g
Lactose 250 g Hydroxypropylcellulose 20 g Light anhydrous silicic
acid 75 g
In a conventional manner, above components are blended, granulated
and regulated using a high-shear granulator, and then thereto is
added light anhydrous silicic acid to give 1% powders.
INDUSTRIAL APPLICABILITY
As explained above, the compounds of the formula (I) show remarked
potent retardation or inhibition of neurodegeneration due to the
hypofunction of glutamic acid receptor and also exhibit low
toxicity, and hence, it can be used for the prevention and/or
treatment of neurodegenerative diseases such as Alzheimer's disease
or schizophrenia in mammals (including human beings) as a medicine
for the prevention and treatment of neurodegenerative diseases.
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